This is a competing renewal of an R01 to develop magnetic seizure therapy (MST) as a novel treatment for psychiatric disorders. Electroconvulsive therapy (ECT) is highly effective for treatment-resistant or intolerant patients, but its cognitive side effects limit its use. The key determinants of efficacy and side effects are electrical dosage and current paths. Better control over them should improve the risk/benefit ratio. However, precise targeting with ECT is hampered by tissue impedance. Tissue is transparent to magnetic fields, thus MST yields better control over the intensity and focality of stimulation and may lower side effects by sparing medial temporal lobe structures. We achieved the aims of the first phase of this project: to develop an MST device for use in nonhuman primates and test its safety. The demonstration of safety supported initial human work with MST beyond the scope of the original aims. The early clinical data confirm that MST has fewer side effects, but also show that the device developed for the monkey is underpowered to perform focal seizure induction in the prefrontal cortex of humans and to exceed seizure threshold adequately to maximize clinical efficacy, two factors critical to the antidepressant efficacy of ECT. Our pilot work shows these limitations can be overcome through device and coil enhancements. A critical question is whether prefrontal suprathreshold MST delivered with the enhanced device maintains its focality or becomes more like ECT in its cognitive effects. Demonstration of safety is needed before clinical work with the upgraded device can begin, presenting a valuable opportunity to study the mechanisms of antidepressant action, and relations among patterns of seizure onset, and neurobiological effects. Key findings to date indicate that electroconvulsive shock (ECS), but not MST, increases cellular proliferation and mossy fiber sprouting in the monkey dentate gyrus. The new proposal will follow up that finding with neuronal markers to study neurogenesis in response to the interventions. This project will upgrade the MST device to permit focal prefrontal seizure induction at suprathreshold levels, test its safety, and compare its neurophysiological, cognitive, and anatomical effects with ECS in monkeys. The electrophysiological effects of ECS and MST will be studied with intracerebral electrodes. Monkeys achieving expert status on a battery of cognitive tasks will provide within-subject data testing whether high dose prefrontal MST spares tasks sensitive to hippocampal function relative to ECS. Differences between MST and ECS in neuropathological effects, hippocampal and frontal cortex stereological cell counts, mossy fiber sprouting and neurogenesis will be examined in a doublemasked, parallel group, random assignment trial in which monkeys will receive ECS, MST, or sham for 6 wks. This work continues the development of a promising new treatment and will inform the mechanisms of action of a well-established treatment, with broader implications for antidepressant action and epilepsy.